Benzopyrido piperidine, piperidylidene and piperazine compounds, compositions, methods of manufacture and methods of use

ABSTRACT

PCT No. PCT/US89/01688 Sec. 371 Date Oct. 26, 1990 Sec. 102(e) Date Oct. 26, 1990 PCT Filed Apr. 26, 1989.Novel benzopyrido piperidiene, piperidylidene and piperazine compounds of the generalized formula &lt;IMAGE&gt;  I  are disclosed as useful for the treatment of asthma, allergy and inflammation. Novel pharmaceutical compositions containing such compounds and processes for producing the compounds are also disclosed.

The present application is the United States national applicationcorresponding to International Application No. PCT/US89/01688 filed Apr.26, 1989 and designating the United States, which PCT application is inturn a continuation-in-part of U.S. application Ser. No. 187,604 filedApr. 28, 1988, which is now abandoned, the benefit of which applicationsis claimed pursuant to the provisions of 35 U.S.C. §§120,363 and 365(c).

BACKGROUND OF THE INVENTION

The present invention relates to certain benzopyrido piperidine,piperazine and piperidylidene compounds, compositions and methods ofuse.

The following references have disclosed oxygen or sulfur in thebridgehead of the three ring portion of the molecule:

Canadian Application 780,443, published in the name of Sandoz PatentsLtd.;

Eire 17764, published Apr. 5, 1964 in the name of Sandoz Patents Ltd.;

European Patent Application 81816337.6, Sandoz A.G., published Mar. 10,1982;

Belgian Application 638,971, Sandoz S.A., published Apr. 21, 1964;

Belgian Application 644,121, Sandoz S.A., published Aug. 20, 1964;

U.S. Pat. No. 4,609,664, issued to Hasspacher on Sept. 2, 1986;

U.S. Pat. No. 3,966,944, issued to Carter on June 29, 1976;

U.S. Pat. No. 3,803,153, issued to Villani on Apr. 9, 1974;

U.S. Pat. No. 3,803,154, issued to Drukker on Apr. 9, 1974;

U.S. Pat. No. 3,325,501, issued to Ettinsen et al. on June 13, 1967;

None of the references disclose substitution on the piperidylidene,piperidine or piperazine nitrogen similar to that set forth below.

SUMMARY OF THE INVENTION

Compounds represented by the structural formula I ##STR2## or apharmaceutically acceptable salt or solvate thereof, wherein:

one of a, b, c and d represents nitrogen or --NR¹¹ --, where R¹¹ is--O⁻, --CH₃ or --(CH₂)_(p) CO₂ H where p is 1 to 3, and the remaining a,b, c and d groups are CH which may be substituted with R¹ or R² ;

R¹ and R² may be the same or different and each independently representshalo, --CF₃, --OR¹⁰, --C(O)R¹⁰, --S(O)_(e) R¹² where e is 0, 1 or 2,--N(R¹⁰)₂, --NO₂, SH, CN, --OC(O)R¹⁰, --CO₂ R¹⁰, --OCO₂ R¹², --NR¹⁰C(O)R¹⁰, alkyl, alkenyl or alkynyl, which alkyl or alkenyl groups may besubstituted with halo, --OR¹⁰ or --CO₂ R¹⁰, or R¹ and R² may togetherform a benzene ring fused to the pyridine ring;

R¹⁰ represents H, alkyl or aryl;

R¹² represents alkyl or aryl;

R³ and R⁴ may be the same or different and each independently representsH or any of the substituents of R¹ and R², or R³ and R⁴ may be takentogether to represent a saturated or unsaturated C₅ -C₇ ring fused tothe benzene ring;

R⁵, R⁶, R⁷ and R⁸ each independently represents H, --CF₃, --CO₂ R¹⁰,--C(O)R¹⁰, alkyl or aryl, which alkyl or aryl may be substituted with--OR¹⁰, --SR¹⁰, --N(R¹⁰)₂, --NO₂, --C(O)R¹⁰, --OC(O)R¹², --OCO₂ R¹²,--CO₂ R¹⁰ and --OPO₃ (R¹⁰)₂, or one of R⁵, R⁶, R⁷ and R⁸ may be taken incombination with R as defined below to represent --(CH₂)_(r) --where ris 1 to 4, said combination being optionally substituted with loweralkyl, lower alkoxy, --CF₃ or aryl, or R⁵ may be combined with R⁶ torepresent ═O or ═S, and/or R⁷ may be combined with R⁸ to represent ═O or═S;

T represents carbon or nitrogen, with the dotted line attached to Trepresenting an optional double bond when T is carbon;

m and n are integers 0, 1, 2, or 3, such that the sum of m plus n equals0 to 3;

when m plus n equals 1, X represents --O--, --S(O)_(e) --where e is 0, 1or 2, --NR¹⁰ --, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --C(S)NR¹⁰ --, --NR¹⁰C(S)--, --CO₂ --or --O₂ C--, where R¹⁰ is as defined above;

when m plus n equals 2, X represents --O--, --S(O)_(e) --where e is 0, 1or 2, or --NR¹⁰ ;

when m plus n represents 0, X can be any substituent for m plus nequalling 1 and X can also be a direct bond, cyclopropylene orpropenylene;

when m plus n equals 3 then X equals a direct bond;

each R^(a) may be the same or different, and each independentlyrepresents H, lower alkyl or phenyl;

Z represents ═O, ═S or ═NR¹³ with R¹³ equal to R¹⁰ or --CN, wherein R¹⁰is as defined above, such that

(a) when Z is O, R may be taken in combination with R⁵, R⁶, R⁷ or R⁸ asdefined above, or R represents H, alkyl, aryl, --SR¹², --N(R¹⁰)₂,cycloalkyl, alkenyl, alkynyl or --D wherein --D representsheterocycloalkyl, ##STR3## wherein R³ and R⁴ are as previously definedand W is O, S or NR¹⁰, and where Y is N or NR¹¹,

said cycloalkyl, alkyl, alkenyl and alkynyl being optionally substitutedwith from 1-3 groups selected from halo, --CON(R¹⁰)₂, aryl, --CO₂ R¹⁰,--OR¹⁴, --SR¹⁴, --N(R¹⁰)₂, --N(R¹⁰)CO₂ R¹⁰, --COR¹⁴, --NO₂ or --D,wherein --D and R¹⁰ are as defined above and R¹⁴ represents R¹⁰,--(CH₂)_(r) OR¹⁰ or --(CH₂)_(q) CO₂ R¹⁰ wherein r is 1 to 4, q is 0 to4;

said alkenyl and alkynyl R groups not containing --OH, --SH or --N(R¹⁰)₂on a carbon in a double or triple bond respectively; and

(b) when Z represents ═S, R represents in addition to those R groupsabove, aryloxy or alkoxy; and

(c) where Z represents ═NR¹³, R represents H, alkyl, aryl, N(R¹⁰)₂,cycloalkyl, alkenyl or alkynyl.

In a preferred embodiment of the invention, d represents nitrogen orNR¹¹, and the a, b, and c groups are CH, which may be substituted withR¹ or R².

Preferred values of R¹ are halo, alkyl and --OR¹⁰ and --N(R¹⁰)₂ whereR¹⁰ is preferably H or alkyl.

Preferred values of R² are identical to those preferred R¹ groups, andmost preferably neither R¹ nor R², or only one of R¹ and R² is present.

Preferred values of R³ and R⁴ are halo, alkyl, --CF₃ or --OR¹⁰, withpreferred R¹⁰ values equal to H or alkyl. More preferably only of R³ andR⁴ is present, and represents halo or alkyl, most preferably halo, andin particular, chloro or bromo.

Preferred values of R⁵, R⁶, R⁷ and R⁸ are H, alkyl or --CO₂ R¹⁰ whereR¹⁰ is H or alkyl. More preferably at most one of R⁵, R⁶, R⁷ and R⁸ isalkyl, the remaining groups being H. Most preferably all four R⁵, R⁶, R⁷and R⁸ are H.

Preferred values of R¹⁰ are H or alkyl, and most preferably H.

The preferred value of R¹¹ is --O³¹.

Preferred values of X when m plus n is zero are a direct bond, --O--,and --S(O)_(e) --, where e is 0, 1 or 2, and most preferably e is zero.

Preferred substituents for X when m plus n is 1 or 2 are --O--and--S(O)_(e) --with e equal to zero.

The preferred substituent for Z is ═O.

Preferred substituents for R are H and alkyl, most preferably alkyl andin particular, lower alkyl.

The preferred substituents for T are carbon with a double bond presentor nitrogen.

Preferred species falling within the scope of the invention include:

1-acetyl-4-(10H-[1]benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidine;

1-acetyl-4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)piperidine;

1-acetyl-4-(10H-[1]-benzoypyrano[3,2-b]pyridine-10-ylidene)piperidene;

4-(10H-[1]-benzopyrano[3,2-b]pyridin-10-ylidene)-1-piperidinecarboxaldehyde;

1-acetyl-4-(5H-benzoypyrano[2,3-b]pyridin-5-ylidene)piperidine;

1-acetyl-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-b]pyridin-12-ylidene)piperidine;

11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine;

11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine1,6-dioxide;

11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine6,6-dioxide;

11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine-6-oxide;

11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine-1,6,6-trioxide;

1-acetyl-4-(9H-indeno[2,1-b]pyridin-9yl)-piperazine; and

1-(4-pyridinylcarbonyl)-4-(5,6,7,12-tetrahydrobenzocycloocta[1,2-b]pyridin-12-ylidene)-piperidineN'-oxide

The invention described herein also encompasses a pharmaceuticalcomposition comprising a compound represented by structural formula I incombination with a pharmaceutically acceptable carrier.

The invention further encompasses a method of treating asthma, allergyand/or inflammation in a mammal in need of such treatment, comprisingadministering a compound of formula I to said mammal in an amounteffective to treat allergy, asthma and/or inflammation, respectively.

The present invention also is directed at the use of a compound offormula I and its pharmaceutically acceptable salts for the preparationof a medicament for the treatment of asthma, allergy and/orinflammation.

The present invention also comprises a method of preparing apharmaceutical composition comprising admixing a compound of formula Iwith a pharmaceutically acceptable carrier.

This invention also is directed at a method of manufacturing a compoundof formula I comprising:

(A) reacting a compound of formula II with a compound of formula III##STR4## where L represents a suitable leaving group; and

(B) reacting a compound of formula V with a suitable compound of formulaIII ##STR5##

(C) Cyclizing a compound of formula XLV to a compound of the formula I.##STR6##

(D) Reacting a compound of formula XXX with a compound of formula XXXIIor XXIX to produce a compound of formula I if R^(c) is Z(C)R. ##STR7##

DETAILED DESCRIPTION

As used herein, the following terms are used as defined below unlessotherwise indicated:

alkyl - (including the alkyl portions of alkoxy, alkylamino anddialkylamino) - represents straight and branched carbon chains andhaving from one to twenty carbon atoms;

lower alkyl - subset of alkyl as defined above, having from one to sixcarbon atoms;

alkanediyl - represents a divalent, straight or branched hydrocarbonchain having from 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms,the two available bonds being from the same or different carbon atomsthereof, e.g., methylene, ethylene, ethylidene, --CH₂ CH₂ CH₂ --, --CH₁CHCH₃, --CH₁ CH₂ CH₃, etc.

cycloalkyl - represents saturated carbocyclic rings branched orunbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms;

heterocycloalkyl - represents a saturated, branched or unbranchedcarbocyclic ring having from 3 to 15 carbon atoms, preferably from 4 to6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 heterogroups selected from --O--, --S--or --NR¹⁰ --(suitable heterocycloalkylgroups including 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl,2- , 3-or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2-or 4-dioxanyl, etc.);

alkenyl - represents straight and branched carbon chains having at leastone carbon to carbon double bond and having from 2 to 12 carbon atoms,preferably from 3 to 6 carbon atoms;

alkynyl - represents straight and branched carbon chains having at leastone carbon to carbon triple bond and having from 2 to 12 carbon atoms,preferably from 2 to 6 carbon atoms;

aryl (including the aryl portion of aryloxy)--represents a carbocyclicgroup having from 6 to 15 carbon atoms and having at least one aromaticring (e.g., aryl is a phenyl ring), with all available substitutablecarbon atoms of the carbocyclic group being intended as possible pointsof attachment, said carbocyclic group being optionally substituted withone or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF₃, amino,alkylamino, dialkylamino, --COOR¹⁰ or --NO₂ ; and

halo - represents fluoro, chloro, bromo and iodo.

Certain compounds of the invention may exist in different isomeric aswell as conformational forms. The invention contemplates all suchisomers and conformers both in pure form and in admixture, includingracemic mixtures.

The compounds of the invention of formula I can exist in unsolvated aswell as solvated forms, including hydrated forms, e.g., hemihydrate. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water, ethanol and the like are equivalent to the unsolvatedforms for purposes of the invention.

As noted above, the pyridine and benzene rings of formula I may containone or more substituents R¹, R², R³ and R⁴. Similarly, the heterocyclicring D may contain one or more of R³ and R⁴. In compounds where there ismore than one such substituent, they may be the same or different. Thuscompounds having combinations of such substituents are within the scopeof the invention. Also, the lines drawn into the rings from the R¹through R⁸ groups indicate that such groups may be attached at any ofthe available positions. For example, the R¹ and R² groups may beattached at the 1, 2, 3 or 4 positions while the R³ and R⁴ groups may beattached at any of the available positions.

Numbering the compounds of the invention varies with the size of thecenter ring. However, numbering the piperidine, piperidylidene orpiperazine remains consistent, with the nitrogen at the bottomdesignated 1', the carbon atom to the left designated 2', and thenumbers increasing in a clockwise fashion. Hence, the carbons to theleft and right of the nitrogen at the bottom are 2' and 6' respectively.

Certain compounds of the invention will be acidic in nature, e.g. thosecompounds which possess a carboxyl or phenolic hydroxyl group. Thesecompounds may form pharmaceutically acceptable salts. Examples of suchsalts may include sodium, potassium, calcium, aluminum, gold and silversalts. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amine, hydroxyalkylamines,N-methylglucamine and the like.

Certain basic compounds of the invention also form pharmaceuticallyacceptable salts, e.g., acid addition salts. For example, the pyrido- orpyrazino-nitrogen atoms may form salts with strong acid, while compoundshaving basic substituents such as amino groups also form salts withweaker acids, Examples of suitable acids for salt formation arehydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, malic, fumaric, succinic, ascorbic, maleic, methane-sulfonicand other mineral and carboxylic acids well known to those in the art.The salts are prepared by contacting the free base form with asufficient amount of the desired acid to produce a salt in theconventional manner. The free base forms may be regenerated by treatingthe salt with a suitable dilute aqueous base solution such as diluteaqueous sodium hydroxide, potassium carbonate, ammonia and sodiumbicarbonate. The free base forms differ from their respective salt formssomewhat in certain physical properties, such as solubility in polarsolvents, but the salts are otherwise equivalent to their respectivefree base forms for purposes of the invention.

All such acid and base salts (e.g. pyridinyl nitrogen salts) areintended to be pharmaceutically acceptable salts within the scope of theinvention and all acid and base salts are considered equivalent to thefree forms of the corresponding compounds for purposes of the invention.

The following processes may be employed to produce compounds of generalstructural formula I.

A. A compound of general formula II may be reacted with compound IIIwith and sometimes without the presence of base to produce compounds ofgeneral structural formula I. ##STR8## Representative examples ofappropriate bases are pyridine and triethylene. L designates a suitableleaving group. For example, if Z is O or S, a compound of compound IIImay be an acyl halide (e.g., L=halo) or acyl anhydride, (e.g., L is##STR9## Alternatively, if the leaving group is hydroxy a couplingreagent may be employed to form Compound I. Examples of coupling agentsinclude N,N'-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl-3-ethylcarbodiimide (DEC) andN,N'-carbonyldiimidazole (CDI). The leaving group may also be alkoxy, inwhich case the compounds of formula I may be produced by refluxing acompound of formula II with an excess of a compound of formula III.

If Z=NR¹³, the compounds of the invention are prepared by substitutinginto the preparative reaction for compound III an appropriatelysubstituted imino chloride or imino ether (e.g., Z=NH, L=Cl or OCH₂CH₃).

Compounds of general formula II may be prepared by cleaving the groupCOOR^(b) from the corresponding carbamates IV, for example, via acidhydrolysis (e.g., HCl) or base hydrolysis (e.g., KOH): ##STR10## whereinR^(b) is a group which does not prevent the cleavage reaction, e.g.,R^(b) is an optionally substituted alkyl such as ethyl, or2,2,2-trichloroethyl.

Alternatively, depending upon the nature of R^(b), as determined by oneskilled in the art, Compound IV may be treated with an organometallicreagent (e.g., CH₃ Li), a reductive reagent (e.g., Zn in acid), etc., toform compounds of formula II.

Compound IV may be prepared from the N-alkyl compound shown as formula Vbelow, in the manner disclosed in U.S. Pat. Nos. 4,282,233 and4,335,036. ##STR11##

There are numerous other methods for converting Compound V to CompoundII. For example, treatment of Compound V with BrCN via von braunreaction conditions would provide nitrile VI as shown below. Subsequenthydrolysis of the nitrile under either aqueous basic or acidicconditions would produce Compound II. This method is preferable whenthere is substitution on the piperidine ring. ##STR12##

B. The compounds of formula I where Z is O or S may be made by analternative process using direct conversion of the N-alkyl compound Vwith an appropriate compound of formula III such as an acyl halide oracyl anhydride. Preferably the reaction is run in the presence of anappropriate nucleophile (e.g. LiI, etc.) and solvent (e.g., toluene,dioxane or xylenes). An appropriate base, may be added, and heating maybe required. Typically, a temperature ranging from 50°-150° C.(preferably 100°-120° C.) is utilized. ##STR13## Compound V is preparedas described in part A above.

When m and n are each zero and X is not a direct bond, the compounds offormula V may be prepared using the teachings of U.S. Pat. Nos.3,803,153; 3,803,154 and 3,325,501. Hence, a ketone of compound VII isreacted with a piperidyl grignard reagent VIII or similar metalatedreagent to form the piperidyl compound IX, which is dehydrated to formcompound X. Compound X may be converted to a compound of the inventionas previously described. ##STR14##

When m and n are each zero, and X represents a direct bond, the reactionscheme below may be utilized. For purposes of illustration, in thereaction scheme below, d has been designated as representing ═N--.However, a, b or c could similarly represented ═N--.

The N-oxide of compound XI may be alkylated (e.g. dimethyl sulfate) inorder to generate a leaving group and then treated with cyanide anion toform the cyanate compound XIII. The cyano derivative XIII can then becyclized to the cyclic ketone XIV using CF₃ SO₃ H or a similar reagent.The reaction is substrate dependent and should be monitored by TLC andusually requires elevated temp. (e.g. 100° C.). The ketone XIV is thenusually reacted with the grignard reagent or other metalated reagent ofthe appropriately substituted --N--alkyl piperidine to form the carbinolXVI. The reaction is usually carried out in an inert solvent such as THFand between -78° C. to +60° C. Other alternatives are possible such asthe reductive coupling of the halo piperidine with the ketone using Nain NH₃. Dehydration of carbinol XVI to XVII can be accomplished using avariety of conditions. Acidic conditions such as CF₃ SO₃ H, PPA or HClin acetic acid are usually preferred. Compound XVII is then converted tocompounds of the invention as previously described. ##STR15##

For compounds of formula I where m plus n is 3 and X is a direct bond,the following general reaction scheme may be used. As described above,for purposes of illustration, d has been designated ═N--, and a, b and care ═CH--or substituted with R¹ or R². However, a, b and c could be usedto designate ═N--therein. ##STR16##

Compound XXV is then converted to I as previously described.

For compounds where X in the bridgehead is other than a direct bond andthe sum of m plus n is 1, 2 or 3, the compounds may generally beprepared by reaction of the appropriate alkyl halide or similarelectrophile with the appropriate nucleophile. This displacement isnormally conducted in the presence of base and an inert solvent, such asTHF or toluene at elevated temperature. In this way, thehaloalkyl-cyanopyridine derivative XXVII may be coupled to anappropriate alcohol, thiol or other appropriately substituted benzenederivative. The leaving group and nucleophile can be interchanged suchthat the pyridine derivative contains the nucleophile X', and thesubstituted benzene derivative contains a leaving group L. CompoundXXVIII can be converted to compound XXIX via the previously describedprocedure. ##STR17##

Alternatively, compounds of the formula I, where T is a carbon atomhaving a double bond may be prepared by a ring closure reaction, whereinthe desired cycloheptene ring is formed by treating compound XL with asuper acid. Suitable super acids for this purpose include, for example,HF/BF₃, CF₃ SO₃ H (triflic acid), CH₃ SO₃ H/BF₃, etc. The reaction canbe performed in the absence of, or with, an inert co-solvent such as CH₂Cl₂. The temperature and time of the reaction vary with the acidemployed. For example, with HF/BF₃ as the super acid system thetemperature may be controlled so as to minimize side reactions, such asHF addition to the exocyclic double bond. For this purpose, thetemperature is generally in the range of from about +5° C. to -50° C.With CF₃ SO₃ H as the super acid system, the reaction may be run atelevated temperatures, e.g., from about 25° C. to about 150° C. and atlower temperatures but the reaction then takes longer to complete.

Generally the super acid is employed in excess, preferably in amounts offrom about 1.5 to about 30 equivalents. ##STR18## A ketone compound offormula XL may be formed by hydrolysis of XLII e.g., such as by reactinga Grignard intermediate of formula XLII with an aqueous acid (e.g.,aqueous HCl). Ia in formula XLII represents chloro, bromo or iodo.##STR19##

The Grignard intermediate XLII is formed by the reaction of the cyanocompound XLIII with an appropriate Grignard reagent XLIV prepared from1-alkyl-4-halopiperidine. The reaction is generally performed in aninert solvent, such as ether, toluene, or tetrahydrofuran, under generalGrignard conditions e.g., temperature of from about 0° C. to about 75°C. Alternatively, other organometallic derivatives of the 1-alkyl-4-halopiperidine can be employed. ##STR20##

An alternative process for the formation of compounds having generalstructural formula I involves direct cyclization of the Compound XLV asshown below. ##STR21##

Cyclization to form the cycloheptane ring is accomplished with a strongacid (e.g., triflic, polyphosphoric, HF/BF₃), and may be performed in aninert solvent, such as ether, toluene or THF. The temperature and timemay vary with the acid employed, as described in process A above.

Compounds of formula XLV where Z=O or S may be prepared by treating acompound of formula XL with an appropriate acyl halide or acylanhydride. Most preferably this reaction is run in the presence of agood nucleophile, such as LiI, in the appropriate solvent, such astoluene, dioxane or xylene, and at a temperature ranging from 50°-150°C., preferably 100°-120° C. ##STR22##

A second method of preparing compounds of formula XLV involves reactingan unsubstituted piperidylidene compound of formula XLVI with theappropriate acyl halide or acyl anhydride with or without the presenceof base, such as pyridine or triethylamine. Alternatively, if L=OH inthe acyl halide or acyl anhydride, then coupling of compound XLVI mayrequire use of a conventional coupling agent, such as DCC or CDI.##STR23##

Compounds of formula XLVI are produced from the corresponding carbamatesof formula XLVII, via acid hydrolysis, using for example, aqueoushydrochloric acid, or base hydrolysis using for example, potassiumhydroxide. Alternatively, some compounds can be prepared by treating thecarbamate, formula XLVII with an organometallic reagent, such as methyllithium or a reductive reagent, such as zinc in acid, etc., dependingupon the nature of the R^(a) group. For example, if R^(a) is a simplealkyl group, CO₂ R^(a) may be cleaved by alkaline hydrolysis at 100° C.##STR24##

The carbamate compounds of formula XLVII may be prepared from theappropriate alkyl compound of formula XL by treatment with achloroformate, preferably in an inert solvent, such as toluene, withwarming to approximately 80° C. Other alternate methods are availablefor the coversion of XL to XLVI as previously described (e.g. Von Braunreaction conditions). Compound XL may then be prepared as describedabove. ##STR25##

PREPARATION OF PIPERAZINE ANALOGS

Compounds of the piperazine type where T is N in formula I, are bestprepared via alkylation of an appropriately substituted piperazinecompound XXX with Compound XXXII containing the appropriatelysubstituted halide (such as Cl, Br, I) or other similar leaving group(tosyloxy or mesyloxy). The reaction usually is conducted in an inertsolvent such as THF or toluene, optionally with a base such astriethylamine or potassium carbonate, typically at a temperature rangeof ambient to reflux to produce Compound XXXIII. ##STR26## In thisreaction R^(c) is H, CO₂ R^(b), C(Z)R or alkyl. The preparation of thetricyclic ring structure where L is Cl is analogous of the proceduredescribed in U.S. Pat. No. 3,409,621. When R^(c) is C(Z)R, compounds ofthe invention are prepared. When R^(c) is H, alkyl or CO₂ R^(b), thecompounds are converted to compounds of the invention by processespreviously described herein.

An alternative route for generating Compound XXXIII is by reductiveamination of the aza ketone XXIX with the appropriately substitutedpiperazine. ##STR27##

The reaction typically is carried out in a polar solvent, such asmethanol or ethanol optionally in the presence of a dehydrating agentsuch as 3/ molecular sieves. The intermediate Schiff base can be reducedto by employing a variety of reducing agents such as NaCNBH₃ orcatalytic hydrogenation, for example, hydrogen over Pd/C.

When R^(c) is C(Z)R, these are the compounds of the present invention.When R^(c) is H, CO₂ R^(b) or alkyl, these are converted to compounds ofthe invention as previously described.

PREPARATION OF SINGLE BOND COMPOUNDS

Compounds where T is a carbon atom having a single bond to the tricyclicstructure may be prepared by the following methods.

A. Compounds having a ketone XL may be converted to the correspondingalcohol XXIV by employing an appropriate reducing agent. The reductioncan be accomplished with a variety of reducing agents (e.g. NaBH₄ orLiAlH₄) in an inert solvent such as THF or ether. Compounds of the typeXL are previously described. ##STR28##

Compounds XXXIV may be cyclized to compound V (where T is carbon and hasa single bond) via a variety of methods. For example, the cyclizationcan be conducted using triflic acid or PPA under conditions similar tothose described for the cyclization previously described. Compound V canthen be converted to compounds of the invention as previously described.

Alternatively, these compounds can be prepared via catalytichydrogenation of the double bond between the piperidylidene carbon atomand the tricyclic ring moiety as described in U.S. Pat. Nos. 3,419,565;3,326,924; and 3,357,986. A variety of catalysts can be used, such asPt, Rh, Ru or Pd on various supports.

(C) A third method for the preparation of the subject compounds is bythe use of the appropriately substituted Grignard reagent VIII (or othercorresponding metalated reagent e.g., organolithium, etc.). CompoundVIII can be reacted with compound XXXII where L is a leaving group (e.g.chloride) to provide the desired Compound XLVIII. ##STR29## Thesereactions generally are conducted in an inert solvent such as ether,toluene, or THF at a temperature range of about -78° to about +50° C.

Alternatively, the metalating substituent and the leaving substituentcould be interchanged and reacted under the same conditions to producethe same compound XLVIII. ##STR30## Compound XLVIII can be converted tocompounds of the invention as previously described. Further details onthese processes are described in U.S. Pat. Nos. 3,419,565; 3,326,924,3,357,986 and in Org. Chem. 50 p. 339 (1986).

D. Alternatively, compounds of formulae XLIX and L, the preparation ofwhich is disclosed in U.S. Pat. Nos. 3,419,565; 3,326,924; and3,357,986, can be used to provide Compound XLVIII. This can beaccomplished by reductive removal of the alcohol under a variety ofconditions e.g. the methods disclosed in J.A.C.S. 104 p. 4976 (1982) andin J. Org. Chem. 50 p. 339 (1985). ##STR31## Compound XLVIII may beconverted to compounds of the present invention as previously described.

To make a compound of the invention where Z represents sulfur, acompound of formula I where Z is oxygen is reacted with P₂ S₅,Lawesson's reagent or another reagent capable of introducing sulfur inplace of oxygen.

The reaction may take place at an elevated temperature in pyridine,toluene or another suitable solvent. Lawesson's reagent has the formula##STR32##

In this and other reactions, conversions of a compound of formula I(Z=O) to another compound of formula I (Z=S) are possible.

In the above processes, it is sometimes desirable and/or necessary toprotect certain R and R¹ to R⁸ groups during the reactions. Conventionalprotecting groups are operable. For example, the groups listed in column1 of the following table may be protected as indicated in column 2 ofthe Table:

    ______________________________________                                        Group                                                                         to be Protected                                                                           Group in Protected Form                                           ______________________________________                                        COOH        COOalkyl, COObenzyl, COOphenyl                                    NH          NCO.sub.2 alkyl, NCO.sub.2 benzyl, NCO.sub.2 CH.sub.2                         CCl.sub.3                                                         CO                                                                                         ##STR33##                                                        OH                                                                                         ##STR34##                                                        NH.sub.2                                                                                   ##STR35##                                                        ______________________________________                                    

Other protecting groups well known in the art also may be used. Afterthe reaction or reactions, the protecting groups may be removed bystandard procedures.

The compounds of the invention possess platelet-activating factor("PAF") antagonistic properties. PAF is an important biochemicalmediator of such processes as platelet aggregation, smooth musclecontraction (especially in lung tissue), vascular permeability andneutrophil activation. Recent evidence implicates PAF as an underlyingfactor involved in airway hyperreactivity. The compounds of theinvention are, therefore, useful whenever PAF is a factor in the diseaseof disorder. This includes allergic diseases such as asthma, adultrespirator distress syndrome, urticaria and also inflammatory diseasessuch as rheumatoid arthritis and osteoarthritis.

The PAF antagonistic properties of these compounds may be demonstratedby use of standard pharmacological testing procedures as describedbelow. These test procedures are standard tests used to determine PAFantagonistic activity and to evaluate the usefulness of said compoundsfor counteracting the biological effects of PAF. The in vitro assay is asimple screening test, while the in vivo test mimics clinical use of PAFantagonists to provide data which simulates clinical use of thecompounds described herein.

A. PAF Antagonism Assay

In vitro Assay

Preparation of platelet-rich plasma (PRP): Human blood (50 ml) wascollected from healthy male donors in an anticoagulant solution (5 ml)containing sodium citrate (3.8%) and dextrose (2%). Blood wascentrifuged at 110×g for 15 min. and the supernatant PRP carefullytransferred into a polypropylene tube. Platelet-poor-plasma (PPP) wasprepared by centrifuging PRP at 12,000×g for 2 min. in a BeckmanMicrofuge B. PRP was used within 3 hours of drawing the blood.

Platelet Aggregation Assay: When an aggregating agent such as PAF isadded to PRP, platelets aggregate. An aggregometer quantifies thisaggregation by measuring light (infra-red) transmission through PRP andcomparing to PPP. The aggregation assays were performed using adual-channel aggregometer (Model 440, Chrono-Log Corp., Havertown,Penna.) PRP (0.45 ml) in aggregometer curettes was continually stirred(37° C.). Solutions of test compounds or vehicle were added to the PRP,and after incubation for 2 min., 10-15)l aliquots of PAF solution wereadded so as to achieve a final concentration of 1-5×10⁻⁸ M. Incubationswere continued until the increase in light transmission reached amaximum (usually about 2 min). Values for inhibition were calculated bycomparing maximal aggregation obtained in the absence and the presenceof the compound. For each experiment, a standard PAF antagonist, such asalprazolam, was used as a positive internal control. The inhibitoryconcentration (IC₅₀) is the concentration of compound in micromoles atwhich 50% of the aggregation is inhibited, as measured by the lighttransmission through each sample of PRP as compared to PPP. The testresults are shown below in Table I.

Since PAF is a known bronchoconstrictive agent in mammals, PAFantagonism can be evaluated by measuring inhibition by the compounds ofthe invention in PAF-induced ronchoconstriction in guinea pigs.

B. PAF-Induced Bronchospasm in Guinea Pigs

In Vivo Assay

Non-sensitized guinea pigs were fasted overnight, and the followingmorning were anesthetized with 0.9 ml/kg i.p. of dialurethane (0.1 g/mlof diallybarbituric acid, 0.4 g/ml of ethylurea and 0.4 g/ml ofurethane). The trachea was cannulated and the animals were ventilated bya Harvard rodent respirator at 55 strokes/min. with a stroke volume of 4ml. A side arm to the tracheal cannula was connected to a Harvardpressure transducer to obtain a continuous measure of intratrachealpressure, which was recorded on a Harvard polygraph. The jugular veinwas cannulated for the administration of compounds. The animals werechallenged i.v. with PAF (0.4 ug/kg in isotonic saline containing 0.25%BSA) and the peak increase in inflation pressure that occurred within 5min. after challenge was recorded. Test compounds were administeredeither orally (2 hrs. prior to PAF as a suspension in 0.4%methylcellulose vehicle) or intravenously (10 min. prior to PAF as asolution in dimethylsulfoxide.

The compounds of the invention also possess antihistaminic propertieswhich may be assessed by test procedure C below. Test procedure C,"Prevention of histaminic-induced lethality" demonstrates basicanti-histaminic activity of representative compounds of structuralformula I. Protection against histamine lethality is indicative ofstrong antihistaminic properties.

Test procedures D, E and F demonstrate the extent of CNS activityinduced by the compounds of the invention. The presence of strong CNSactivity indicates a high probability of sedation caused by thecompounds, a typically undesirable side effect of antihistiamines.Consequently, a low level of CNS activity is preferred in mostcircumstances.

C. Antihistamine Activity Assay

Prevention of Histamine-Induced Lethality in Guinea Pigs. The compoundsmay also be evaluated for antihistamine activity by their ability toprotect female albino guinea pigs (250-350 g) against death induced bythe intravenous injection of histamine dihydrochloride at 1.1 mg/kg,which is approximately twice the LD₉₉. Doses of the antagonists areadministered orally to separate groups of fasted animals 1 hour prior tothe challenge with histamine and protection from death recorded for 30minutes after histamine. ED₅₀ values were determined for each drug byprobit analysis.

CNS Activity Assay

D. Antagonism of Physostigmine Lethality. The physostigmine-inducedlethality test is indicative of CNS activity and the test described is amodification of the technique reported by COLLIER et al., Br. J.Pharmac., 32, 295-310 (1968). Physostigmine salicylate (1.0 mg/kg s.c.)produces 100% lethality when administered to mice grouped 10 per plasticcage (11×26×13 cm). Test agents were administered orally 30 minutesprior to physostigmine. The number of survivors were counted 20 minutesafter physostigmine administration.

E. Antagonism of Acetic Acid Writhing. The acetic acid writhing test isa second test useful for determining CNS activity, and is essentiallythat described by HENDERSHOT and FORSAITH, J. Pharmac. Exp. Ther., 125,237-240 (1959), except that acetic acid rather than phenylquinone wasused to elicit writhing. Mice were injected with 0.6% aqueous aceticacid at 10 mg/kg i.p. 15 minutes after oral administration of the testdrug. The number of writhes for each animal was counted during a 10minute period starting 3 minutes after acetic acid treatment. A writhewas defined as a sequence of arching of the back, pelvic rotation andhind limb extension.

F. Antagonism of Electro-Convulsive Shock (ECS). The ECS test is a thirdtest useful for determining CNS activity. For the ECS test, amodification of the method of TOMAN et al., J. Neurophysiol., 9, 231-239(1946), was used. One hour after oral administration of the test drug orvehicle, mice were administered a 13 mA, 60 cycle a.c. electroconvulsantshock (ECS) for 0.2 seconds via corneal electrodes. This shock intensityproduces tonic convulsions, defined as extension of the hind limbs, inat least 95% of vehicle-treated mice.

Of the above test procedures for measuring CNS activity, thephysotigmine-induced lethality test is believed to be a major index ofnon-sedating characteristics potency which is believed to contribute tosedative activity.

In the Table I below PAF antagonism data are presented for previouslyknown compounds and for compounds of the present invention.

                  TABLE I                                                         ______________________________________                                                                      Percent PAF                                     Compound              Dose    Antagonism                                      ______________________________________                                         ##STR36##             >50*    50%                                             ##STR37##            >175*    50%                                             ##STR38##            50 μM                                                                               13%                                             ##STR39##            50 μM 25 μM                                                                      47% 32%                                         ##STR40##            50 μM                                                                               20%                                             ##STR41##            50 μM 12 μM                                                                      92% 50%                                         ##STR42##             5.5 μM n = 0 32 μM n = 1  3 μM n = 2 12                             μM    50% 50% 50% 50%                                 ##STR43##            27 μM                                                                               50%                                             ##STR44##            50 μM  5 μM                                                                     100%  52%                                        ##STR45##            50 μM  5 μM                                                                     100%  47%                                        ##STR46##            50 μM  5 μM                                                                     100%  79%                                       ______________________________________                                         *previously known compounds                                              

As seen from the data in Table I, the compounds of structural formula Iexhibit PAF antagonist activity. Consequently, it is within the scope ofthis invention to use each of these compounds when clinicallyappropriate.

For preparing pharmaceutical composition from the compounds described bythis invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient on a weight/weight basis. Suitable solid carriers areknown in the art, e.g. magnesium carbonate, magnesium stearate, talc,sugar, lactose. Tablets, powders, cachets and capsules can be used assolid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection.

Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.01 mg to 2000 mg, more preferably fromabout 1 mg. to 100 mg, according to the particular application. Theappropriate dosage can be determined by comparing the activity of thecompound with the activity of a known PAF antogonist.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

The amount and frequency of administration of the compounds of theinvention and the pharmaceutically acceptable salts thereof will beregulated according to the judgement of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regiment for oral administration is from 10 mg to 2000 mg/daypreferably 10 to 750 mg/day, in two to four divided doses to achieverelief of the symptoms. The dosage ranges for the treatment of allergyand inflammation are generally considered to be the same. Hence oraldosage ranges will be similar, injectable dosage ranges will be similar,etc.

The following examples are intended to illustrate, but not to limit, thepresent invention.

PREPARATIVE EXAMPLE 1 A.1-Methyl-4-(10H-[1]benzothiopyrano[3,2-b]-10-hydroxypyridinyl]piperidine##STR47##

Suspend benzo[b]thiopyrano[2,3-b]-pyridin-10-one (1.3 g; 6.1 mmole) indry tetrahydrofuran ("THF") (30 ml) at room temperature and under anargon atmosphere. Add N-methyl-4-piperidinyl magnesium chloride (1.2eq., 4.8 ml of 1.5M reagent in THF), forming a dark solution. Stir atroom temperature for 1 hour.

Quench the reaction with concentrated NH₄ Cl and extract with ethylacetate. Wash the organic portions with brine and dry over Na₂ SO₄.Remove the solvent and chromatograph the resultant liquid (5%→10% CH₃OH/NH₃ in CH₂ Cl₂) to produce a yellowish solid which may becrystallized from pentane (0.80 g).

B.1-Methyl-4-(10H-[1]benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidine##STR48##

Warm the title compound of part A above (780 mg) in H₂ SO₄ (85%, 20 ml)to 105° C. in an oil bath for 20 minutes. Pour the reaction mixture intoice water and basify with NaOH (25%). Extract with CH₂ Cl₂ and wash thecombined organic portions with brine. Dry over Na₂ SO₄ to produce ayellowish glass (408 mg).

Purify with flash chromatography over (10%T15% CH₃ OH in CH₂ Cl₂) toproduce a yellowish glassy solid (290 mg).

C. 1-Cyano-4-(10H-[1]benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidine##STR49##

Add the title compound of part B above (291 mg) to a solution ofcyanogen bromide (158 mg, 1.5 eq) in dry benzene (8.5 ml) at roomtemperature, and stir for 3 hours.

Remove the solvent under high vacuum to produce a solid and flashchromatograph (5% CH₃ OH in CH₂ Cl₂) to produce the title compound as ayellowish solid (220 mg, m.p. 192°-193° C.).

D.1-Aminocarbonyl-4-(10H-[1]benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidineand 4-(10H-[1]benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidine##STR50##

Reflux a mixture of the title compound of part C above (210 mg) and 29%aq HCl (20 ml) for 24 hours. Pour the reaction mixture onto ice andbasify with 25% aqueous NaOH. Extract the mixture with CH₂ Cl₂ (2×200ml) and wash the combined organic portions with brine. Dry over Na₂ SO₄,filter and remove the solvent to yield a glassy solid.

Chromatograph on SiO₂ (230-400 mesh), eluting with 10%T15% CH₃ OH in CH₂Cl₂ to yield the title compounds in two fractions, fraction 1 containingthe N--H compound 1A as a yellowish solid (146 mg, m.p. 162°-163° C.),and fraction 2 containing the aminocarbonyl substituted compound 1B asan off-white solid (32 mg, 185°-187° C.).

PREPARATIVE EXAMPLE 2 A.1-Methyl-4-(10H-[1]benzopyrano[3,2-b]pyridin-10-ylidene)piperidine##STR51##

Prepare1-methyl-4-(10H-[1]benzopyrano[3,2-b]pyridin-10-ylidene)piperidine, asdescribed in U.S. Pat. No. 3,803,153.

B. 1-Cyano-4-(10H-[1]benzopyrano[3,2-b]pyridin-10-ylidene)piperidine##STR52##

Stir a solution of cyanogen bromide (22.9 g, 0.196 m) in dry benzene(300 ml) at room temperature, and add a solution of the title compoundof part A above (54.5 g, 0.196M) in benzene (300 ml).

Filter the resulting solution after 3 hr. and concentrate to dryness toproduce an off-white solid (44.0 g, m.p. 172°-175° C.).

Recrystallize the product from acetonitrile to afford the titlecompound.

C. 4-(10H)-[1]benzopyrano[3,2-b]pyridin-10-ylidene) piperidine ##STR53##

Reflux a mixture of the title compound from part B above (44.0 g,0.152M), glacial acetic acid (1140 ml), conc. HCl (115 ml) and H₂ O (760ml) for 20 hours. Remove excess acetic acid and H₂ O under reducedpressure, cool and basify with Na₂ CO₃. Extract with chloroform and dryover Na₂ SO₄. Concentrate to dryness and chromatograph on silica gelusing acetonitrile to produce the title compound (27.0 g, m.p. 158°-160°C.).

PREPARATIVE EXAMPLE 3 A. 3-(3-phenylpropyl)pyridine ##STR54##

Heat a mixture of 2-phenylethyl 3-pyridinyl ketone (19.5 g, 0.092M),NaOH (8.0 g), hydrazine hydrate (8 ml, 85% in H₂ O) and diethyleneglycol (125 ml) to 240° C. for 4 hours.

Extract with benzene (1X), then diethyl ether (1X). Wash the combinedorganic extracts with H₂ O (3X), remove the solvent and distill toproduce the title compound (15.8 g, b.p. 130°-131° C. at 2 mmHg).

B. 3-(3-phenylpropyl)pyridine-N-oxide ##STR55##

Add cold H₂ O₂ (101 ml, 30%) to a cold solution of the title compoundfrom part A above (166 g, 0.84M) in CH₃ CO₂ H (252 ml).

Heat to 60° C. for 24 hours and pour into ice water. Basify with NH₄ OH,bringing the total volume to 2.0L. The product separates out as an oil,which solidifies upon cooling. Filter and dissolve the filtrate inCHCl₃.

Remove the solvent and crystallize the product from benzene/hexane toproduce the title compound (63.0 g, m.p. 34°-35° C.).

C. 2-Cyano-3-(phenyl-n-propyl)pyridine ##STR56##

Add dimethyl sulfate (76 g, 0.6M) to the title compound from part Babove (171.5 g) and stir on a steam bath for 3 hours. Add H₂ O (200 ml)and cool the solution, then add the solution dropwise to a solution ofNaCN (92 g) in H₂ O (260 ml) at 0° C. under a N₂ atmosphere. Allow thesolution to remain at 0° C. for 4 hours, then stir the mixture for 12hours at room temperature, while maintaining the reaction under an N₂atmosphere. Extract the resultant brownish solution with CHCl₃.Concentrate the combined organic portions and purify via distillation.Crystallize the title compound from the appropriate fractions usingbenzene/pet ether (34.0 g, m.p. 50°-52° C.).

D. 12H-benzo[b]-5,6,7,12-tetrahydrocycloocta[2,3-b]pyridin-12-one##STR57##

Stir the title compound from part C above (5.0 g) with polyphosphoricacid (250 g) while heating to 240° C., then reduce heat to 220° C. andmaintain for 2 hours.

Pour the reaction mixture into ice water and basify with NaOH. Extractwith diethyl ether and remove the solvent to form the title compound incrude form (4.0 g, m.p. 141°-145° C.) which may be recrystallized from2-butanone to produce the title compound as a white solid (m.p.153°-155° C.).

E. 1-Methyl-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-b]-2-hydroxypyridinyl)piperidine ##STR58##

Dissolve sodium (2.7 g, 0.12M) in NH₃ (200 ml) and stir for 20 minutes.Add the title compound from part D above, (13 g, 0.058M) in THF (105 ml)slowly and stir for 5 minutes. Add a solution of4-chloro-1-methylpiperidine (7.8 g, 0.058M) in THF (25 ml) and continuestirring.

Add NH₄ Cl (5.0 g) and NH₃ (75 ml) and continue stirring for anadditional 2 hours.

Concentrate the mixture to dryness, then partition over water andbenzene. Extract with additional benzene. Remove the solvent to form aviscous tan residue.

Triturate the tan residue with pet ether and isopropyl ether. Cool thesolution and decant off the liquids from the precipitate to obtain thetitle compound as a white solid (5 g, m.p. 122°-124° C.).

F.1-Methyl-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta-[1,2-b]pyridin-12-ylidene)piperidine##STR59##

Combine the title compound from part E above (1.413 g) with CH₃ CO₂ H(12 ml), acetyl chloride (7 ml) and acetic anhydride (3.5 ml) and heatto 100° C. under an N₂ atmosphere.

After 3 hours concentrate the mixture in vacuo and pour the residue intoNaOH (1N). Extract with CH₂ Cl₂ (3X). Combine the organic portions, dryover MgSO₄, filter and rotary evaporate to dryness.

Purify by flash chromatography (5% CH₃ OH/NH₃ in CH₂ Cl₂) to produce thetitle compound which may be crystallized from pentane (1.014 g).

G.1-(1,1,1-Trichloroethoxycarbonyl)-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-b]pyridin-12-ylidene)piperidine ##STR60##

Combine the title compound from part F above (1.008 g, 3.31 mmol) with(CH₃ CH₂)₃ N (0.70 ml) and dry toluene (30 ml) at 90° C. under an argonatmosphere. Add dropwise 2,2,2-trichloroethylcarbonyl chloride (1.80 ml)over 20 minutes. Maintain the temperature at 90° C. for 1.67 hours, thencool to room temperature and pour into aqueous NaOH (1N).

Extract the reaction mixture with CH₂ Cl₂ (3X), combine the organicportions and dry over MgSO₄.

Filter and rotary evaporate to dryness.

Purify by flash chromatography (CH₃ OH 2% in CH₂ Cl₂) and combineappropriate fractions to obtain the title compound.

H.4-(5,6,7,12-tetrahydrobenzocycloocta[1,2]pyridin-12-ylidene)piperidene##STR61##

Combine the title compound from part G above and glacial acetic acid (20ml) under an N₂ atmosphere at 90°-90° C. with zinc dust (2.12 g).

After 3 hours, cool the reaction to room temperature, filter and rotaryevaporate to dryness. Basify the residue with NaOH (1N) and extract withCH₂ Cl₂ (4X). Combine the organic portions, dry over MgSO₄, filter androtary evaporate to dryness. Purify by flash chromatograph (5%T7% CH₃OH/NH₃ in CH₂ Cl₂) and collect the appropriate fractions to yield thetitle compound as a glass (603 mg).

PREPARATIVE EXAMPLE 4 A. 2-Cyano-3-(bromomethyl)pyridine ##STR62##

Combine 2-cyano-3-methylpyridine (11.8 g), N-bromosuccinimide ("NBS")(26.8 g, 1.0 eq) and aza(bis)isobutyronitrile ("ABIN") (180 mg) in dryCCl₄ (300 ml). Reflux the mixture.

Pour the mixture into water, basify with NaOH and extract with CH₂ Cl₂.Wash the organic portion with water, dry, filter and concentrate toobtain a liquid. Chromatograph the product, eluting with diethylether/hexane (30%). Combine the appropriate fractions to obtain the monobromo compound (5.01 g) as a yellowish solid.

B. 2-Cyano-3-(3-chlorophenoxymethyl)pyridine ##STR63##

Stir a solution of the title compound of part A above (0.71 g, 3.6mmol), NaI (54 mg, 0.1 eq) and Cs₂ CO₃ (1.17 g, 1.0 eq) in dry acetone(17 ml, dried over MgSO₄) at room temperature for 5 minutes, then add3-chlorophenol (463 mg) via a syringe.

Reflux over an oil bath for 4.5 hrs.

Filter and wash the filtrate with dry acetone. Concentrate the filtrate,suspend in diethyl ether, and refilter to obtain a brown solid which isthe title compound in crude form. Triturate with pentane, and resuspendin diisopropyl ether (40 ml) with charcoal, and heat on a steam bath.

Filter and evaporate the solvent to obtain the title compound, whichcrystallizes to form a white solid (640 mg, m.p. 70°-72° C.).

C. 8-Chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-one ##STR64##

Stir the title compound from part B above (6.1 g) in CF₃ SO₃ H (60 ml)at room temperature for 3 hours. Upon completion, quench with H₂ O andconc. HCl (30% and continue stirring for 0.5 hours.

Warm to 35° C. for 0.5 hours. Basify with NaOH (25%) and extract withCH₂ Cl₂ (2X). Wash with brine (2X), filter and dry over Na₂ SO₄.

Triturate the resulting semisolid (6.35 g) with diisopropyl ether andseparate the isomers via flash chromatography (3% EtoAc in hexanes).Combine the appropriate fractions to obtain the title compound as asolid (4.902 g, m.p. 139.5°-140.5°), and the 10-chloro compound as asolid (462 mg, m.p. 100°-100.5° C.).

D.1-methyl-4-(8-chloro-11-hydroxy-5,11-dihydro[1]benzoxepino[4,3b]pyridinyl)piperidine##STR65##

Slowly add a solution of the title compound from part C above (3.47 g)in dry tetrahydrofuran ("THF") (37 ml) to the grignard reagent (11.9 ml,1.2M) and stir at room temperature for 0.5 hrs.

Quench the reaction with ice and NH₄ Cl. Extract the solution with CH₂Cl₂ (2X), dry, filter and concentrate to obtain the title compound.Chromatograph the product on silica gel (5%T7.5% CH₃ OH/NH₃ in CH₂ Cl₂)to obtain the title compound as a glass (2.56 g).

E.1-Methyl-4-(8-chloro-5,11-dihydro[1]benzoxepin[4,3-b]pyridin-11-ylidene)piperidine ##STR66##

Stir the title compound from part D above (934 mg) in CF₃ SO₃ H (20 ml)at room temperature for 15 min. Raise temperature to 45° C. on an oilbath and maintain for 1.25 hrs. Cool to room temperature and pour themixture into ice water. Basify with dilute NaOH, and extract with CH₂Cl₂ (2X). Wash with brine (1X) and dry over Na₂ SO₄ to obtain the titlecompound as a brown glass.

Purify by combining with charcoal in ethyl acetate, then filter andremove solvent to obtain a yellowish brown solid.

Recrystallize from ethyl acetate and diisopropyl ether to obtain thetitle compound as an off-white solid (540 mg, m.p. 168°-170° C.).

F.1-Ethoxycarbonyl-4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)piperidine##STR67##

Dissolve the title compound from part E above (474 mg, 1.45 mmol) intoluene (10 ml) and add (CH₃ CH₂)₃ N (0.656 ml). Warm and maintain thereaction at 80°-85° C. and slowly add ClCO₂ CH₂ CH₃ (1.242 ml). Maintainthe reaction at 80°-85° C. while stirring for 3 hours.

Quench the reaction with H₂ O and extract with ethyl acetate (2×100 ml).Wash with brine, separate and dry over Na₂ SO₄. Remove the solvent andpurify via flash chromatography, eluting with ethyl acetate in hexane(40T60%) to yield the title compound as an off-white solid, which may bepurified by trituration with pentane and diisopropyl ether (428 mg, m.p.118°-120° C.).

G.4-(8-Chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)piperidine##STR68##

Dissolve the title compound from part F above (333.8 mg) in CH₃ CH₂ OH(5 ml) and add 14% aqueous KOH. Reflux under an argon atmosphere for 19hours.

Quench the reaction with H₂ O and extract with CH₂ Cl₂ (3×100 ml). Washwith brine (1×100 ml), dry over Na₂ SO₄ and filter. Remove the solventto yield a glassy off-white solid.

Recrystallize with ethyl acetate/diisopropyl ether to yield the titlecompound as a white powder. (161.5 mg, m.p.. 166°-176° C.).

PREPARATIVE EXAMPLE 5 A. 1,2,6-trimethyl-4-chloropiperidine ##STR69##

The starting material, 1,2,6-trimethyl-4-piperidinol, may be prepared bythe method disclosed in Archi Kem, Volume 27, pages 189-192 (1955). To acooled (ice-bath) solution of 1,2,6-trimethyl-4-piperidinol (12.2 g,85.3 mmol) in 120 mL of dry benzene is slowly add thionylchloride (17mL, 233 mmole). The dark reaction mixture is warmed to 70° C. for 20min. The reaction is cooled and then suspended in water followed byfiltration. The filtrate is extracted once with diethylether. Theaqueous layer is separated and the basified with 30% NaOH solution. Theproduct is then extracted twice with CH₂ Cl₂, washed once with brine,dried (Na₂ SO₄), filtered and the solvent removed to produce a crudebrown liquid which is distilled (2-4 mmHg, 62°-64° C.) to give the titlecompound (8.0 g).

B.2,6-Dimethyl-4-(10H-[1]benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidine##STR70##

Slowly drip the chloride, 1,2,6-trimethyl-4-chloropiperidine, (4.2 g, 26mmol) into a solution of dry THF (18 mL) containing Mg (633 mg, 26.3mm). The Grignard reagent is formed after heating for 6 hours at 70° C.

Add the Grignard to the appropriate ketone in Preparative Example 1 andconvert to the final intermediate product as described therein, therebyproducing the title compound.

PREPARATIVE EXAMPLE 6 A. 3,5-DIMETHYLPYRIDINIUM N-OXIDE ##STR71##

Slowly add a solution of 285 mL (1.31 mol) of 35% peracetic acid to astirred solution of 149 g (1.39 mol) of 3,5-dimethylpyridine andmaintain at 85° C. during addition. Allow the temperature of the mixtureto drop to about 35° C.

After partial removal of 185 ml of acetic acid via distillation undervacuum, wash with NaHSO₄ solution and then neutralize with 10% NaOHsolution to pH of about 7. Extract the product with CH₂ Cl₂ to obtainthe title compound as a white solid (142 g)

B. 1-METHOXY-3,5-DIMETHYLPYRIDINIUM METHYL SULFATE ##STR72##

Slowly add dimethylsulfate (42.0 g, 0.33 mol) to a mechanically stirredsolid of 41.0 g (0.33 mol) of 3,5-dimethylpyridinium N-oxide. Heat themixture on a steam bath for 1 hr. Apply vacuum while cooling to producethe title compound as a brownish solid.

C. 2-CYANO-3,5-DIMETHYLPYRIDINE ##STR73##

Cool a solution of sodium cyanide (49.0 g, 0.999 mol, 3.0 eq.) in 135 mLof water to 0° C., (air free) and drip 1-methoxy-3,5-dimethyl pyridiniummethyl sulfate (83.0 g, 0.33 mol) in 100 mL water (air free) over 11/4hr., keeping the temperature below 3° C. Filter the mixture and washwith water to give 40 g of the title compound which may berecrystallized from isopropyl ether and pentane (4:1) (m.p. 61°-62° C.).

D. N-(1,1-dimethylethyl)-3,5-dimethyl-2-pyridinecarboxamide ##STR74##

Stir a solution of 2-cyano-3,5-dimethylpyridine (20.3 g, 0.153 mol) in100 mL of acetic acid and 20 mL of conc. sulfuric acid over 10 minutes.Add t-butanol (20 ml.) over an additional 15 minutes. Warm the solutionto 75° C. and maintain for 30 minutes. Cool to room temperature andbasify with 25% NaOH. Extract the product (3X) with ethyl acetate (600mL). Combine the organic portions and wash (1X) with brine. Dry (Na₂SO₄), filter and concentrate in vacuo to produce the title compound as ayellowish oil (31.26 g).

E.N-(1,1-DIMETHYLETHYL)-3-[3-(4-FLUOROPHENYL)PROPYL]-5-METHYL-2-PYRIDINECARBOXAMIDE ##STR75##

Cool a solution of N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamidein dry THF to -40° C. and add 2 equivalents of n-butyl lithium. Add alarge excess of sodium bromide and stir for 15 minutes. Add 1 eq. of4-fluorophenethyl chloride and stir for 2.5 hours while warming to -5°C. Quench the reaction with water and extract the product twice withethyl acetate, then wash with brine (2X). Dry the organic phase over Na₂SO₄, filter and remove the solvent to produce the title compound.

F. 3-[3-(4-FLUOROPHENYL)PROPYL]-5-METHYL-2-PYRIDINE CARBONITRILE##STR76##

Heat the title compound of part E above in POCl₃ to 110° C. under anargon atmosphere for several hours. Pour the reaction mixture onto iceand basify with NaOH (50%) solution. Extract the mixture with ethylacetate (3x) and wash with water. Wash with brine and dry over Na₂ SO₄.Remove the solvent and pass the residue through a coarse SiO₂ (60-200mesh) column to produce the title compound as a white solid.

G.3-METHYL-10-FLUORO-5,6,7,12-TETRAHYDROBENZO[6,7]CYCLOOCTA[1,2-b]PYRIDIN-12-ONE##STR77##

Cyclize the title compound of part F in polyphosphoric acid at 240° C.for several hours. Pour onto ice and basify with NaOH solution (50%).Extract the product with chloroform (3x) and wash with brine. Dry theorganic phase with Na₂ SO₄, filter and remove the solvent to produce thetitle compound.

H.4-(3-Methyl-10-fluoro-5,6,7,12-tetrahydrobenzocycloocta[1,2-b]pyridin-12-ylidene)piperidine##STR78## The carbonyl compound of part G above may be converted to thetitle compound as described in preparation example 3 above. PREPARATIVEEXAMPLE 7 A. 2-Cyano-3-(bromomethyl)pyridine ##STR79##

The title compound was prepared as described in Preparative Example 4,Part A.

B. 2-Cyano-3-(3-chlorophenylthiomethyl)pyridine ##STR80##

To a stirred, cloudy solution of sodium methoxide (14.7 g, 0.27 mol) inmethanol (450 mL), contained in a water bath, add a solution of3-chlorothiophenol (39.5 g, 0.27 mol) in methanol (95 mL). To theresultant solution add a solution of the title compound of Part A above(48.9 g, 0.25 mol) in methanol (195 mL), and stir the reaction mixtureat room temperature for 1 h.

Concentrate the reaction mixture under reduced pressure, add 500 mL ofether to the residue, stir, and filter to remove sodium bromide.Evaporate ether under reduced pressure to obtain the title compound asan amber oil, which may be used without further purification in thefollowing ring-closure process (Part C).

C. 8-Chloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridin-11-one ##STR81##

Stir a solution of the title compound from Part B above (49.7 g, 0.19mol) in CF₃ SO₃ H (500 mL) for 3.5 h at 95° C. Allow the reactionmixture to cool below 60° C. and pour onto crushed ice (1500 mL). Stirthe mixture for 0.5 h and add sufficient aqueous sodium hydroxide (220mL of 50% solution) to raise the pH to 9.

Extract the aqueous solution with ethyl acetate (1x), saturate withsodium chloride, and extract again (2x) with ethyl acetate. Wash thecombined extracts with brine (3x), filter, and dry over anhydrous MgSO₄.

Remove solvent under reduced pressure, and chromatograph the residualmaterial on silica gel, eluting with ethyl acetate-hexanes (3:2), toobtain the title ketone as a tan solid, mp 186°-187° c.

D.1-Methyl-4-(8-chloro-11-hydroxy-5,11-dihydro[1]benzothiepino[4,3-b]pyridinyl)piperidine##STR82##

With cooling in an ice-water bath, add a suspension of the title ketonefrom Part C above (13.4 g, 51.2 mmol) in dry tetrahydrofuran (=THF; 52mL) to a stirred solution (55 mL of approximately 1M) in THF of theGrignard reagent derived from 1-methyl-4-chloropiperidine. Stir theresultant mixture for 1 h at room temperature.

Quench the reaction by cooling the mixture to 10° C. in an ice-waterbath and adding saturated aqueous ammonium chloride solution (50 mL).Add methylene chloride (100 mL), and stir the mixture for a few minutes.Filter the mixture through Celite, and wash the filter cake withmethylene chloride. Combine the original filtrate and washes, separatethe methylene chloride phase, and extract the aqueous phase (2x) withadditional methylene chloride. Combine the extracts, wash with brine(2×75 mL), and dry over anhydrous sodium sulfate. Filter, strip thefiltrate under reduced pressure, and chromatographed the residue onsilica gel, eluting with methylene chloride-methanol-ammonium hydroxide(90:9:0.5), to obtain the title compound as an off-white to pale pinksolid with mp 158.5°-159.5° C.

E. 1-Methyl-4-(8-chloro-5,11-dihydro-8 1]benzothiepino[4,3-b]pyridin-11-ylidene)piperidine ##STR83##

Heat a solution of the title compound from Part D above (5.04 g, 13.9mmol) in CF₃ SO₃ H at 45° C. for 10.5 h. Cool the reaction solution toroom temperature, and pour it into a stirred ice-water mixture. Maintaincooling in an ice-water bath, and add with stirring aqueous sodiumhydroxide (130 mL of a 50% solution). Extract the solution withmethylene chloride (3x), wash the combined extracts successively withwater (2x) and brine (1x), dry over anhydrous sodium sulfate, andevaporate solvent under reduced pressure. Purify the residual glass bychromatographing on silica gel, eluting with methylenechloride-methanol-ammonium hydroxide (90:9:0.25), and triturating thesolid thus isolated in acetonitrile. Filter to obtain the title compoundas a light tan solid, containing 0.08 mole methylene chloride, mp175°-177° C.

F.1-Ethoxycarbonyl-4-(8-chloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridin-11-ylidene)piperidine##STR84##

To a stirred solution of the title compound from Part E above (1.44 g,4.2 mmol) and triethylamine (966 mg, 9.5 mmol) in dry toluene (27 mL),maintained at 80° C., add dropwise ethyl chloroformate (2.78 g, 25.6mmol). After one hour, add more triethylamine (480 mg, 4.7 mmol), andcontinue heating at 80° C. for an additional hour.

Cool the reaction mixture to 50° C., add ethyl acetate (15 mL), washsuccessively with water (2x) and brine (1x), and dry over anhydrousmagnesium sulfate. Filter, evaporate the filtrate under reducedpressure, and purify by chromatographing the residual solid on silicagel. Elute first with ethyl acetate-hexanes (9:1); then rechromatographthe partially purified material with ethyl acetate-hexanes (1:1) toobtain the title compound as an off-white solid with mp 154°-157° C.

G.4-(8-Chloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridin-11-ylidene)piperidine##STR85##

Reflux for 21.5 h in an inert gas atmosphere a solution of the titlecompound from Part F above (720 mg, 1.87 mmol) and potassium hydroxide(2.0 g, 35.6 mmol) in ethanol (20 mL)-water (2 mL).

Cool to room temperature, dilute with methylene chloride (20 mL), andwash successively with water (4x) and brine (1x). Dry the solution overanhydrous sodium sulfate, filter, and evaporate the filtrate underreduced pressure to obtain the title compound as an off-white solid, mp206.5°-215° c.

EXAMPLE 11-Acetyl-4-(10H-[1]benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidine##STR86##

Dissolve the title compound from Preparative Example 1, part D (131 mg)in dry CH₂ Cl₂ (6 ml) and add pyridine (57 )l) in CH₂ Cl₂ (1 ml). Coolin an ice bath under an argon atmosphere and add dropwise CH₃ C(O)Cl(50)L) in CH₂ Cl₂ (2 ml). Stir the reaction while warming to roomtemperature over 30 minutes.

Dilute the reaction with CH₂ Cl₂ and quench with dilute NaOH (0.5N, 50ml). Separate off the organic layer and extract with CH₂ Cl₂ (1X). Washthe organic layer with brine (1X), dry over Na₂ SO₄, filter and removethe solvent. Azeotrope with toluene (1X) to yield a glassy solid (145mg) which may be triturated with ethyl acetate and pentane.

Purify with flash chromatography, eluting with 5% CH₃ OH in CH₂ Cl₂ toyield the title compound as a white glassy solid (140 mg).

In the same manner1-acetyl-2,6-dimethyl-4-(10H-[1]benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidinewas prepared from the title compound of preparative example 5, part B.

EXAMPLE 2 4-(10H-[1]benzopyrano[3,2-b]pyridin-10-ylidene)-1-piperidenecarboxaldehyde ##STR87##

Reflux the title compound of Preparative Example 2, part C (13.1 g) inethylformate (400 ml) on a steam bath for 12 hours.

Remove excess ethyl formate under vacuum to produce a brown oil.

Triturate the resultant brown oil with ethyl acetate to produce thetitle compound as a crystalline solid, which may be recrystallized fromethyl acetate. (7.5 g, m.p. 142°-145° C.).

EXAMPLE 31-Acetyl-4-(10H-[1]benzopyrano[3,2-b]pyridin-10-ylidene)piperidine##STR88##

Dissolve the title compound of Preparative Example 2, Part C (304 mg) indry CH₂ Cl₂ (10 ml) and pyridine (0.456 ml).

Cool in an ice bath under an argon atmosphere and slowly add aceticanhydride (0.505 ml) in CH₂ Cl₂ (2 ml). Stir the reaction while warmingto room temperature over 30 minutes to yield the title compound in crudeform.

Purify via flash chromatography eluting with 0%T3% CH₃ OH in CHCl₃.Combine the appropriate fractions after removing the solvent, andtriturate the solid with pentane (2X) to yield the title compound as awhite solid (178 mg, m.p. 124°-126° C.).

EXAMPLE 4 1-Acetyl-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-b]pyridin-12-ylidene)piperidine ##STR89##

Dissolve the title compound of Preparative Example 3, Part H (302 mg,1.04 mmol) in dry CH₂ Cl₂ (10 ml) at 0° C. under an N₂ atmosphere. Addacetic anhydride (110 )l) dropwise.

After 4.5 hours, quench the reaction by pouring into aqueous NaOH (1N).Extract with CH₂ Cl₂ (3X). Combine the organic portions, dry over MgSO₄,filter and rotary evaporate to dryness to produce the title compound asa glass (331 mg).

In the same manner1-acetyl-4-(3-methyl-10-fluoro-5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-b]pyridin-12-ylidene)piperidinewas prepared from the title compound of preparative example 6, part G.

EXAMPLE 5 1-Acetyl-4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)piperidine ##STR90##

Dissolve the title compound from Preparative Example 4, part G (113 mg)in CH₂ Cl₂ (4 ml). Add pyridine (58.4 )l) and cool the reaction. Addacetyl chloride (51.4 )l) and stir under an argon atmosphere for 1 hour.

Pour the reaction mixture in water and extract with CH₂ Cl₂. Wash thecombined organic portions with brine, and dry over Na₂ SO₄.

Remove the solvent to produce the title compound as an off-white glass.

Purify the resultant compound with flash chromatography, eluting with 5%CH₃ OH in CH₂ Cl₂ to produce the title compound as a white glass (110mg).

EXAMPLE 61-METHOXYACETYL-4-(5,6,7,12-TETRAHYDROBENZO[6,7]CYCLOOCTA[1,2-b]PYRIDIN-12-YLIDENE)PIPERIDINE##STR91##

Dissolve the title compound of Preparative Example 3, part H, andpyridine in dry CH₂ Cl₂ at 0° C. under an argon atmosphere. Add 1.1equivalents of methoxyacetyl chloride dropwise, and slowly warm to roomtemperature. After 1.5 hours take up the mixture in CH₂ Cl₂ and washwith brine. Dry over Na₂ SO₄, filter, and concentrate in vacuo to obtaina residue, which may be purified via flash chromatography.

EXAMPLE 7 1-Acetyl-4-(8-chloro-5,11-dihydro[1]-benzothiepino[4,3-b]pyridin-11-ylidene)piperidine ##STR92##

To a stirred solution of the title compound from Preparative Example 7,Part G, (470 mg, 1.43 mmol) and pyridine (225 mg, 2.84 mmol) inmethylene chloride (21 mL), maintained at 10° C., add acetyl chloride(220 mg, 2.83 mmol) and stir the resultant solution at 10° C. for 45minutes.

Add ice water (20 mL), and basify the mixture with 2.5M aqueous sodiumhydroxide. Separate the layers, and extract the aqueous layer withmethylene chloride (2x). Combine the extracts, wash with brine (1x), dryover anhydrous magnesium sulfate, filter, and evaporate the filtrateunder reduced pressure. Chromatograph the residual glass on silica gel,eluting with methylene chloride-methanol-ammonium hydroxide (90:9:0.25);triturate the yellow powder thus obtained with hexanes; and filter toobtain the title compound as a very pale yellow hemihydrate, mp80°-83.5° C. (dec).

EXAMPLE 8 1-Acetyl-4-(8-chloro-5,11-dihydro[1]-benzothiepino[4,3-b]pyridin-11-ylidene)piperidine-6-oxide ##STR93##

Add solid 3-chloroperoxybenzoic acid (59.4 mg of 80-85%, 0.293 mmol) toa stirred, cold (-50° C.) solution of the title compound from Example 7above (109 mg, 0.293 mmol) in methylene chloride (7 mL), and stir theresultant solution at -50° C. for 1 h.

Wash the cold solution successively with 1.1M aqueous sodium bicarbonate(1x), water (2x), and brine (1x). Dry over anhydrous magnesium sulfate,filter, and evaporate solvent from the filtrate under reduced pressure.Triturate the residue with ether, and filter to obtain the 1/4 hydrateof the title compound as a white solid, mp 209°-211° C. (dec).

EXAMPLE 9 (a) 1-Acetyl-4-(8-chloro-5,11-dihydro[1]-benzothiepino[4,3-b]pyridin-11-ylidene)piperidine-6,6-dioxide; (b)1-Acetyl-4-(8-chloro-5,11-dihydro[1]-benzothiepino[4,3-b]pyridin-11-ylidene)piperidine-1,6,6-trioxide; (c)1-Acetyl-4-(8-chloro-5,11-dihydro[1]-benzothiepino[4,3-b]pyridin-11-ylidene)piperidine-1,6-dioxide; ##STR94##

(a) Add solid 3-chloroperoxybenzoic acid (98.3 mg of 80-85%, K0.48 mmol)to a stirred, cold (-50° C.) solution of the title compound from Example7 (202 mg, 0.546 mmol) in methylene chloride (6 mL). Stir for 1 h at-50° C., add a second quantity of 3-chloroperoxybenzoic acid (98.3 mg,K0.48 mmol), and stir for another hour at -50° C. Add a third portion of3-chloroperoxybenzoic acid (9.4 mg, K0.046 mmol), and allow the reactionmixture to warm to room temperature. Stir at room temperature for 1 h,add a fourth quantity of the oxidant (9.4 mg, K0.046 mmol), and stir fora final 1 hour period.

Wash the reaction mixture successively with 1.1M aqueous sodiumbicarbonate (1x) and brine (1x). Dry over anhydrous sodium sulfate,filter, and evaporate solent from the filtrate under reduced pressure.Chromatograph the residue on silica gel, eluting with methylenechloride-methanol-ammonium hydroxide (98:5:0.25) to obtain fractionscorresponding to title compounds (a), (b), and (c), respectively.Rechromatograph on silica gel the fractions enriched in compound (a),eluting with methylene chloride-methanol-ammonium hydroxide (99:1:0.13)to obtain the title sulfone as a 3/4 hydrate, mp 225°-228° C. (dec).

(b) Triturate in ether the solid derived from the chromatographicfractions containing compound (b), filter, and crystallize the solidfrom methanol-isopropyl ether. Triturate the crystalline product withether, and filter to obtain the 3/4 hydrate of the title sulfone N-oxideas a white solid, mp 238°-240° C. (dec).

(c) Triturate in ether the solid derived from the chromatographicfractions containing compound (c), and filter to obtain the titlesulfoxide-N-oxide as a tan solid, mp 180°-184° C. (dec).

EXAMPLE 101-(4-Pyridinylcarbonyl)-4-(5,6,7,12-tetrahydrobenzocycloocta[1,2-b]pyridin-12-ylidene)piperidineN'-oxide ##STR95##

To a mixture of 4.50 g (15.5 mmol) of4-(5,6,7,12-tetrahydrobenzocycloocta[1,2-b]pyridin-12-ylidene)piperidine, 2.19 g (15.7 mmol) of isonicotinic acid N-oxide, and 2.33 g(17.2 mmol) of 1-hydroxybenzotriazole hydrate in 30 mL of dry methylenechloride at -15° C. and under a nitrogen atmosphere was added dropwiseover 25 min. a solution of 3.26 g (16.9 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 60 mL ofdry methylene chloride. The reaction mixture was slowly allowed to warmto room temperature. After 3 hours the mixture was poured into asolution of 10% aqueous sodium dihydrogen phosphate and extracted withmethylene chloride (3x). The combined organic portions were dried overMgSO₄, filtered, and concentrated in vacuo to give a product which waspurified via flash chromatography to give 1-(4-pyridinylcarbonyl)-4-(5,6,7,12-tetrahydrobenzocycloocta[1,2-b]pyridin-12-ylidene)piperidineN-oxide as a colorless glass.

EXAMPLE 11 1-Acetyl-4-(9H-indeno[2,1-b]pyridin-9-yl)piperazine ##STR96##

Intermediate compound XIV can be reduced with a reducing agent such asNaBH₄ to produce the corresponding alcohol. This can be converted to thecorresponding 9-methyl sulfonyl indeno [2,1-b]pyridine.

A mixture of 68 mg (0.28 mmol) of 9-methylsulfonyl-9Hindeno[2,1-b]pyridine, 76 mg of K₂ CO₃ (0.55 mmol), and 59 mg (0.46mmol) of N-acetyl piperazine in 10 ml of acetonitrile was heated atapproximately 40° C. under a nitrogen atmosphere for 4 hours. Themixture was poured into water and extracted 3X with EtOAc. The organiclayers were combined, washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified via flash chromatography(2-3% MeOH/NH₃ in CH₂ Cl₂) to give 52 mg (65%) of the title compound asan off white solid.

The following are examples of pharmaceutical dosage forms which containa compound of the invention. As used therein, the term "active compound"is used to designate the compound1-acetyl-4-(12H-benzo[b]cycloocta[3,2-b]pyridin-12-ylidene)piperidine.The scope of the invention in its pharmaceutical composition aspect isnot to be limited by the examples provided, since any other compound ofstructural formula I can be substituted into the pharmaceuticalcomposition examples.

Pharmaceutical Dosage Form Examples

    ______________________________________                                        Example A                                                                     Tablets                                                                       No.   Ingredient       mg/tablet  mg/tablet                                   ______________________________________                                        1.    Active Compound  100        500                                         2.    Lactose USP      122        113                                         3.    Corn Starch, Food Grade,                                                                        30         40                                               as a 10% paste in                                                             Purified Water                                                          4.    Corn Starch, Food Grade                                                                         45         40                                         5.    Magnesium Stearate                                                                              3          7                                                Total            300        700                                         ______________________________________                                    

Method of Manufacture

Mix item nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulatethe mixture with item no. 3. Mill the damp granules through a coarsescreen (e.g., 1/4") if needed. Dry the damp granules. Screen the driedgranules if needed and mix with item no. 4 and mix for 10-15 minutes.Add item no. 5 and mix for 1-3 minutes. Compress the mixture toappropriate size and weight on a suitable tablet machine.

    ______________________________________                                        Example B                                                                     Capsules                                                                      No.   Ingredient       mg/capsule mg/capsule                                  ______________________________________                                        1.    Active Compound  100        500                                         2.    Lactose USP      106        123                                         3.    Corn Starch, Food Grade,                                                                        40         70                                         4.    Magnesium Stearate NF                                                                           4          7                                                Total            250        700                                         ______________________________________                                    

Method of Manufacture

Mix item nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Additem no. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

While the present invention has been described in connection withcertain specific embodiments thereof, it will be evident to one ofordinary skill in the art that many alternatives, modifications andvariations may be made. All such alternatives, modifications andvariations are intended to be included within the spirit and scope ofthe invention.

What is claimed is:
 1. A compound represented by the structural formula##STR97## or a pharmaceutically acceptable salt or solvate thereof,wherein: one of a, b, c and d represents nitrogen or --NR¹¹, where R¹¹is --O⁻, --CH₃, or --(CH₂)_(p) CO₂ H where p is 1 to 3, and theremaining a, b, c and d groups are CH which may be optionallysubstituted with R¹ or R² ;R¹ and R² may be the same or different andeach independently represents halo, --CF₃, --OR¹⁰, --C(O)R¹⁰, --S(O)_(e)R¹² where e is 0, 1 or 2, --N(R¹⁰)₂, --NO₂, SH, CN, --OC(O)R¹⁰, --CO₂R¹⁰, --OCO₂ R¹², --NR¹⁰ C(O)R¹⁰, C₁ -C₂₀ alkyl, C₂ -C₁₂ alkenyl or C₂-C₁₂ alkynyl, which alkyl or alkenyl groups may be substituted withhalo, --OR¹⁰ or --CO₂ R¹⁰, or R¹ and R² may together form a benzene ringfused to the pyridine ring; R¹⁰ represents H, C₁ -C₂₀ alkyl or C₆ -C₁₅aryl; R¹² represents C₁ -C₂₀ alkyl or C₆ -C₁₅ aryl; R³ and R⁴ may be thesame or different and each independently represents H or any of thesubstituents of R¹ and R², or R³ and R⁴ may be taken together torepresent a saturated or unsaturated C₅ -C₇ ring fused to the benzenering; R⁵, R⁶, R⁷ and R⁸ each independently represents H, --CF₃, --CO₂R¹⁰, --C(O)R¹⁰, C₁ -C₂₀ alkyl or C₆ -C₁₅ aryl, which alkyl or aryl maybe substituted with --OR¹⁰, --SR¹⁰, --N(R¹⁰)₂, --NO₂, --C(O)R¹⁰,--OC(O)R¹², --OCO₂ R¹², --CO₂ R¹⁰ and --OPO₃ (R¹⁰)₂, or one of R⁵, R⁶,R⁷ and R⁸ may be taken in combination with R as defined below torepresent --(CH₂)_(r) --where r is 1 to 4, said combination beingoptionally substituted with C₁ -C₆ alkyl, C₁ -C₆ alkoxy, --CF₃ or C₆-C₁₅ aryl, or R⁵ may be combined with R⁶ to represent ═O or ═S, and/orR⁷ may be combined with R⁸ to represent ═O or ═S; T represents carbon ornitrogen, with the dotted line attached to T representing an optionaldouble bond when T is carbon; m and n are integers 0, 1, 2, or 3, suchthat the sum of m plus n equals 0 to 3; when m plus n equals 1, Xrepresents --O--, --S(O)_(e) --wherein e is 0, 1 or 2, --NR¹⁰ --,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --C(S)NR¹⁰ --, --NR¹⁰ C(S)--, --CO₂ --or--O₂ C--, where R¹⁰ is a defined above; when m plus n equals 2, Xrepresents --O--, --S(O)_(e) --where e is 0, 1 or 2, or --NR¹⁰ ; when mplus n represents 0, X can be any substituent for m plus n equalling 1and X can also be a direct bond, cyclopropylene or propenylene; when mplus n equals 3 then X equals a direct bond; each R^(a) may be the sameof different, and each independently represents H, C₁ -C₆ alkyl orphenyl; Z represents ═O, ═S or ═NR¹³ with R¹³ equal to R¹⁰ or --CN,wherein R¹⁰ is as defined above, such that(a) when Z is O, R may betaken in combination with R⁵, R⁶, R⁷ or R⁸ as defined above, or Rrepresents H, C₁ -C₂₀ alkyl, C₆ -C₁₅ aryl, --SR¹², --N(R¹⁰)₂, C₃ -C₂₀cycloalkyl, C₂ -C₁₂ alkenyl, C₂ -C₁₂ alkynyl or --D wherein --Drepresents C₃ -c₁₅ heterocycloalkyl, ##STR98## wherein R³ and R⁴ are aspreviously defined and W is O, S or NR¹⁰, and where Y is N or NR¹¹, saidcycloalkyl, alkyl, alkenyl and alkynyl being optionally substituted withfrom 1-3 groups selected from halo, --CON(R¹⁰)₂, C₆ -C₁₅ aryl, --CO₂R¹⁰, --OR¹⁴, --SR¹⁴, --N(R¹⁰)₂, --N(R¹⁰)CO₂ R¹⁰, --COR¹⁴, --NO₂ or --D,wherein --D and R¹⁰ are as defined above and R¹⁴ represents R¹⁰,--(CH₂)_(r) OR¹⁰ or --(CH₂)_(q) CO₂ R¹⁰ wherein r is 1 to 4, q is 0 to4; said alkenyl and alkynyl R groups not containing --OH, --SH or--N(R¹⁰)₂ on a carbon in a double or triple bond respectively; and(b)when Z represents ═S, R represents in addition to those R groups above,C₆ -C₁₅ aryloxy or C₁ -C₂₀ alkoxy; and (c) where Z represents ═NR⁵⁰, Rrepresents H, C₁ -C₂₀ alkyl, C₆ -C₁₅ aryl, N(R¹⁰)₂, C₃ -C₂₀ cycloalkyl,C₂ -C₁₂ alkenyl or C₂ -C₁₂ alkynyl.
 2. A compound as defined in claim 1wherein d represents nitrogen or NO, and the a, b and c groups are CHwhich may be substituted with R¹ or R².
 3. A compound as defined inclaim 1 further characterized by one of R³ and R⁴ being halo, alkyl,--CF₃ or --OR¹⁰.
 4. A compound as defined in claim 3 furthercharacterized by R⁵, R⁶, R⁷ and R⁸ being H or alkyl.
 5. A compound asdefined in claim 4 further characterized by m plus n equalling 1, and Xrepresenting --O--, --S(O)_(e) --, where e is 0, 1 or
 2. 6. A compoundas defined in claim 4 above further characterized by m plus n beingzero, and X representing a direct bond, cyclopropylene, propenylene,--O--or --S(O)_(e) --with e equal to 0, 1 or
 2. 7. A compound as definedin claim 4 above further characterized m plus n equalling 3 and X beinga direct bond.
 8. A compound as defined in claim 1 further characterizedby T being carbon and the dotted line attached to T representing adouble bond.
 9. A compound as defined in claim 1 further characterizedby T being nitrogen.
 10. A compound as defined in claim 1 furthercharacterized by Z being O and R representing H, alkyl, or D.
 11. Acompound as defined in claim 1 having thename:1-acetyl-4-(10H-[1]benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidine;1-acetyl-4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3]pyridin-11-ylidene)piperidine;1-acetyl-4-(10H-[1]benzopyrano[3,2-b]pyridin-10-ylidene)piperidine;4(10H-[1]benzopyrano[3,2-b]pyridin-10-ylidene)-1-piperidinecarboxaldehyde;1-acetyl-4-(5H-[1]benzopyrano[2,3-b]pyridin-5-ylidene)piperidine;1-acetyl-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-b]pyridin-12-ylidene)piperidine;1-methoxyacetyl-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-b]pyridin-12-ylidene)piperidine;11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine;11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine1,6-dioxide;11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine6,6-dioxide;11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine-6-oxide;11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine-1,6,6-trioxide; 1-acetyl-4-(9H-indeno[2,1-b]pyridin-9-yl)piperazine;and1-(4-pyridinylcarbonyl)-4-(5,6,7,12-tetrahydrobenzocycloocta[1,2b]pyridin-12-ylidene)piperidineN'-oxide.
 12. A method of treating asthma, allergy and/or inflammationcomprising administering to a mammal in need of such treatment anantiallergic effective amount of a compound as defined in claim
 1. 13. Apharmaceutical composition comprising a compound of formula I as definedin claim 1 in combination with a pharmaceutically acceptable carrierwherein the active compound in a unit dose is about 0.01 mg to 2000 mg.